EGAGenomicsPeiyong Jianghttps://ega-archive.org/dacs/EGAC00001000078EGAEGA DAC EGAC00001000078EGAjiangpeiyong@cuhk.edu.hkWe performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double-stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non-IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non-IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.Fetal DNA is present in the plasma of pregnant women. Massively parallel sequencing of maternal plasma DNA has been used to detect fetal trisomies 21, 18, 13 and selected sex chromosomal aneuploidies noninvasively. Case reports describing the detection of fetal microdeletions from maternal plasma using massively parallel sequencing have been reported. However, these previous reports were either polymorphism-dependent or used statistical analyses which were confined to one or a small number of selected parts of the genome. In this report, we reported a procedure for performing noninvasive prenatal karyotyping at 3 Mb resolution across the whole genome through the massively parallel sequencing of maternal plasma DNA. This method has been used to analyze the plasma obtained from 6 cases. In three cases, fetal microdeletions have been detected successfully from maternal plasma. In two cases, fetal microduplications have been detected successfully from maternal plasma. In the remaining case, the plasma DNA sequencing result was consistent with the pregnant mother being a carrier of a microduplication. Simulation analyses were performed for determining the number of plasma DNA molecules that would need to be sequenced and aligned for enhancing the diagnostic resolution of noninvasive prenatal karyotyping to 2 Mb and 1 Mb. In conclusion, noninvasive prenatal molecular karyotyping from maternal plasma by massively parallel sequencing is feasible and would enhance the diagnostic spectrum of noninvasive prenatal testing.The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions.Circulating tumor-derived cell-free DNA (ctDNA) analysis offers an attractive noninvasive means for detection and monitoring of cancers. Evidence for the presence of cancer is dependent on the ability to detect features in the peripheral circulation that are deemed as cancer-associated. We explored approaches to improve the chance of detecting the presence of cancer based on sequence information present on ctDNA molecules. We developed an approach to detect the total pool of somatic mutations. We then investigated if there existed a class of ctDNA signature in the form of preferred plasma DNA end coordinates. Cell-free DNA fragmentation is a nonrandom process. Using plasma samples obtained from liver transplant recipients, we showed that liver contributed cell-free DNA molecules ended more frequently at certain genomic coordinates than the nonliver-derived molecules. The abundance of plasma DNA molecules with these liver-associated ends correlated with the liver DNA fractions in the plasma samples. Studying the DNA end characteristics in plasma of patients with hepatocellular carcinoma and chronic hepatitis B, we showed that there were millions of tumor-associated plasma DNA end coordinates in the genome. Abundance of plasma DNA molecules with tumor-associated DNA ends correlated with the tumor DNA fractions even in plasma samples of hepatocellular carcinoma patients that were subjected to shallow-depth sequencing analysis. Plasma DNA end coordinates may therefore serve as hallmarks of ctDNA that could be sampled readily and, hence, may improve the cost-effectiveness of liquid biopsy assessment.Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients.Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics.Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments.Noninvasive prenatal molecular karyotyping from maternal plasma.Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma.Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing.[Acute puerperal kidney failure. A new syndrome?].Chan Rebecca W Y RW, Jiang Peiyong P, Peng Xianlu X, Tam Lai-Shan LS, Liao Gary J W GJ, Li Edmund K M EK, Wong Priscilla C H PC, Sun Hao H, Chan K C Allen KC, Chiu Rossa W K RW, Lo Y M Dennis YMYu Stephanie C Y SC, Jiang Peiyong P, Choy Kwong W KW, Chan Kwan Chee Allen KC, Won Hye-Sung HS, Leung Wing C WC, Lau Elizabeth T ET, Tang Mary H Y MH, Leung Tak Y TY, Lo Yuk Ming Dennis YM, Chiu Rossa W K RWSun Kun K, Jiang Peiyong P, Chan K C Allen KC, Wong John J, Cheng Yvonne K Y YK, Liang Raymond H S RH, Chan Wai-kong WK, Ma Edmond S K ES, Chan Stephen L SL, Cheng Suk Hang SH, Chan Rebecca W Y RW, Tong Yu K YK, Ng Simon S M SS, Wong Raymond S M RS, Hui David S C DS, Leung Tse Ngong TN, Leung Tak Y TY, Lai Paul B S PB, Chiu Rossa W K RW, Lo Yuk Ming Dennis YMJiang Peiyong P, Chan Carol W M CW, Chan K C Allen KC, Cheng Suk Hang SH, Wong John J, Wong Vincent Wai-Sun VW, Wong Grace L H GL, Chan Stephen L SL, Mok Tony S K TS, Chan Henry L Y HL, Lai Paul B S PB, Chiu Rossa W K RW, Lo Y M Dennis YMJiang Peiyong P, Sun Kun K, Tong Yu K YK, Cheng Suk Hang SH, Cheng Timothy H T THT, Heung Macy M S MMS, Wong John J, Wong Vincent W S VWS, Chan Henry L Y HLY, Chan K C Allen KCA, Lo Y M Dennis YMD, Chiu Rossa W K RWKJenssen H HTsang Jason C H JCH, Vong Joaquim S L JSL, Ji Lu L, Poon Liona C Y LCY, Jiang Peiyong P, Lui Kathy O KO, Ni Yun-Bi YB, To Ka Fai KF, Cheng Yvonne K Y YKY, Chiu Rossa W K RWK, Lo Yuk Ming Dennis YMDFresh, Carcinoma, Frozen Plasma, Liver, DNS, Fresh Frozen Plasma, (Deoxyribonucleotide)n, Blood, DNAn+1, Cell Carcinoma, Liver Cell, adult hepatoma, Double-Stranded, Hepatomas, Plasmas, Liver Cell Carcinoma, Deoxyribonucleic acids, (Deoxyribonucleotide)n+m, Frozen Plasmas, Cell Carcinomas, Client., Deoxyribonucleic Acid, HCC, Liver Cell Carcinomas, Adult Liver Cancer, Adult Liver, ds-DNA, desoxyribose nucleic acid, Carcinomas, Plasma, Fresh Frozen Plasmas, Fresh Frozen, Blood Plasma, thymus nucleic acid, Adult Liver Cancers, Hepatocellular carcinoma, Liver Cancer, Hepatoma, adult primary hepatocellular carcinoma, Liver Cancers, portion of plasma, Double Stranded, Deoxyribonucleic acid, Cancers, Adult, Hepatocellular Carcinoma, Patient, Clients, Blood Plasmas, ds DNA, Desoxyribonukleinsaeure, Hepatocellular, Double-Stranded DNA, (Deoxyribonucleotide)m, DNA, deoxyribonucleic acids, DNAn, Hepatocellular Carcinomas, plasma, CancerHongkong, grupo, Kowloon, Activity, Laboratory, acide nucleique, Asian, Research Priorities, New Territories, East Asian, Far East, acides nucleiques, Priority, nucleic acids, Nucleic Acid, Research Activities, group., NA, University, Research Activity, Eastern, Laboratory Research, East, East Asian Peoples, Asian People, Research and Development, Priorities, Acid, Eastern Asian Peoples, Nukleinsaeure, ensemble, Research, Rest, Eastern Asian People, acido nucleico, Nucleic, Far East Asian, Activities, set, East Asians, Far East Asians, People, acidos nucleicos, grupos, Eastern Asians, Nukleinsaeuren, Eastern Asian, Acids, Development and Research, Research Priority, Chinese, groupe, Gruppeextent, IgG Antibody, Activity, determination, Systemic, supply, Blood, B-cell receptor complex, protein, congenital defects, Tumor, aplasia, Readability, diseases, Gamma Globulin, diseases and disorders, Prenatal Cell-Free DNA Screening, protein aggregate, present in fewer numbers in organism, imprinted and ancient gene protein, Fresh Frozen Plasmas, Fresh Frozen, increased, thymus nucleic acid, human disease, CG12918, membrane bound, proportionality to, hypoplasia, Noninvasive Prenatal Screening, decreased, column, Prenatal Testing, malignant neoplasm, Libman-Sacks Disease, s, Homo sapiens disease, Double-Stranded DNA, Malignancies, deoxyribonucleic acids, Libman-Sacks, DNAn, B-lymphocyte receptor complex, plasma, Tumors, Frozen Plasma, completeness, Double-Stranded, antibodies, Plasmas, deformities, results, (Deoxyribonucleotide)n+m, shortened, Benign, IgG3, IgG4, IgG1, IgG2, Diseases, desoxyribose nucleic acid, lupus nephritis, excess lymphocyte low molecular weight DNA, atresia, IgG, lupus, Lupus Erythematosus Disseminatus, susceptibility to, malformations, proportionality, Benign Neoplasms, rate, Malignant Neoplasms, disease, immunoglobulin, Prenatal Diagnosis, B cell receptor accessory molecule complex, Patient, IgG2A, anomalies, IgG2B, GT, ds DNA, B lymphocyte receptor complex, DNA, short, E430016J11Rik, 7S, accessory, Fresh, other disease, Libman Sacks Disease, DNS, Fresh Frozen Plasma, (Deoxyribonucleotide)n, Immunoglobulin, SLE, Sle, Neoplasms, Prenatal, number, Benign Neoplasm, Gene, protein-containing complex, Ximpact, Malignant, supernumerary, Deoxyribonucleic acids, Systemic Lupus Erythematosus, antibody, Antibody, BCR complex, cfDNA Screening, Client., Deoxyribonucleic Acid, reduced, subnumerary, Gene Products, disease or disorder, defects, immunoglobulin complex, Blood Plasma, proportion, Immunoglobulin GT, IgG(T), Malignancy, distribution, stubby, Double Stranded, Deoxyribonucleic acid, Prenatal Cell Free DNA Screening, decreased number, DmelCG12918, non-neoplastic, Neoplasias, Noninvasive Prenatal Diagnosis, Clients, Blood Plasmas, disorder, (Deoxyribonucleotide)m, Methylations, Cancer, Disease, Prenatal Screening, Malignant Neoplasm, protein complex, DNAn+1, Proteins, disorders, Systemic lupus erythematosus, medical condition, Lupus Erythematosus, Client, impact-a, Frozen Plasmas, MT, LIBMAN SACKS DIS, native protein, agenesis, excess LMW-DNA, chemical analysis, Protein, Neoplasm, condition, imprinted and ancient gene protein homolog, IMPACT, supply and distribution, methylation, ds-DNA, Prenatal cfDNA Screening, opsonin activity, Plasma, primary cancer, increased number, Polyglobin, portion of plasma, Cancers, Understanding, malignant tumor, Noninvasive, Protein Gene Products, present in greater numbers in organism, Gene Proteins, Indexes, birth defects, cardinality, 7S Gamma Globulin, Desoxyribonukleinsaeure, B cell receptor activity, quotient, Allerglobuline, assay, General activity, RWDD5, NeoplasiafalseThe Chinese University of Hong Kong (CUHK) Circulating Nucleic Acids Research Group (CNARG)Data Access Committee EGAC00001000078

2025-1-9

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